Sphingosine 1-phosphate (S1P) mediates numerous biological processes. Accordingly, potential new drug candidates may be specific agonists and antagonists of S1P receptors.
Chemical manipulation of myriocin led to the development of a new immunosuppressive sphingosine analog known as FTY720 (2-amino-2-[2-(4-octylphenylethyl]-1,3-propanediol), which is phosphorylated in vivo and acts as an agonist for several G-protein coupled sphingosine 1-phosphate receptors.

The (S)-phosphate of FTY720 is an analog of S1P and is a potent agonist of the S1P-type 1 receptor (and three other S1P receptors), but does not activate the S1P-type 2 receptors on the surface of thymocytes and lymphocytes. FTY720 possesses more potent immunosuppressive activity without inhibiting sphingolipid biosynthesis and host immune defense responses to most infectious agents. FTY720 inhibits lymphocyte trafficking in vivo, promoting sequestration of lymphocytes into lymph nodes and impairing S1P type 1-mediated migration of lymphocytes between secondary lymphoid tissues and the blood, rendering the cells unresponsive to S1P and external signals that direct these cells to sites of inflammation.
FTY720 is a potent inhibitor of several autoimmune diseases such as type 1 diabetes and arthritis. As FTY720 and its (S)-phosphate activate S1P receptors and stimulate various signaling pathways, they appear to have utility for treatment of a variety of pathological conditions, including angiogenesis, inflammation, respiratory distress syndrome, and autoimmune diseases.
Although FTY720 failed to improve efficacy for preventing renal allograft rejection in phase III clinical studies, a different purpose has been found for its potential use. Phase III clinical trials are underway to examine the utility of FTY720 for potential treatment of systemic lupus erythematosus and multiple sclerosis. (S)-FTY720-phosphate stimulated, via induction of ERK1/2 and Akt phosphorylation, the survival of progenitor cells that give rise to myelin-producing mature oligodendrocytes. Therefore, in addition to its immunosuppressive function, FTY720 shows promise as a therapeutic agent in treatment of multiple sclerosis via replenishment of lost oligodendrocytes, thus promoting remyelination.
FTY720 was recently found to enhance pulmonary endothelial cell barrier integrity by a mechanism that appears to be different than that utilized by sphingosine 1-phosphate, which also enhances endothelial cell vascular barrier integrity. FTY720 also has potential therapeutic action in eicosanoid-driven inflammatory disorders.
The exact mechanism of action of FTY720 is under debate. As a result, new derivatives are needed to examine the mechanism of FTY720 in cells, and luminescent derivatives offer the advantage of permitting investigators to monitor intra- and intercellular trafficking of FTY720.